EP0184841B1 - 1,4-Dihydropyridinderivate, Verfahren zu ihrer Herstellung und diese enthaltende pharmazeutische Zusammensetzungen - Google Patents

1,4-Dihydropyridinderivate, Verfahren zu ihrer Herstellung und diese enthaltende pharmazeutische Zusammensetzungen Download PDF

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Publication number
EP0184841B1
EP0184841B1 EP85115829A EP85115829A EP0184841B1 EP 0184841 B1 EP0184841 B1 EP 0184841B1 EP 85115829 A EP85115829 A EP 85115829A EP 85115829 A EP85115829 A EP 85115829A EP 0184841 B1 EP0184841 B1 EP 0184841B1
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European Patent Office
Prior art keywords
ester
dihydropyridine
dimethyl
dicarboxylic acid
ethyl
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EP85115829A
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English (en)
French (fr)
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EP0184841A3 (en
EP0184841A2 (de
Inventor
Hiroyasu Koyama
Yoshikuni Suzuki
Koichiro Hagihara
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Nisshin Seifun Group Inc
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Nisshin Seifun Group Inc
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Priority claimed from JP60269302A external-priority patent/JPH0631223B2/ja
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Publication of EP0184841A3 publication Critical patent/EP0184841A3/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to new compounds having valuable vasodilating and blood pressure lowering effects, etc., to processes for their preparation and to their use as vasodilating and antihypertensive agents.
  • 1,4-dihydropyridine derivatives having cardiovascular activity are known. It is known to obtain 1,4-dihydro-2,6-dimethyl-3-phenylpyridine-3,5-dicarboxylic acid diethyl ester by reacting 2-benzylideneacetoacetic acid ethyl ester, ,8-aminocrotonic acid ethyl ester or acetoacetic acid ethyl ester and ammonia, as reported in Ber. Deutsch Chem. Ges. 31, 743(1971).
  • DE-A-2117517 and 2117573 disclose that similar compounds can be used as coronary arteriodilating and antihypertensive agents, and inter alia 1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)pyridine-3,5-dicarboxylic acid dimethyl ester disclosed therein has been used extensively under the name of Nifedipine. Since commercial success of Nifedipine, a large number of compounds having similar chemical structure have been developed and these compounds are disclosed in US Patents 3,574,843; 4,264,611; 3,799,934; 4,239,893; 4,317,768; 4,044,141 and 4,258,042; EPO Appln. 0012180; and French Patent 2,182,983.
  • the present invention results from efforts to develop new compounds with more improved pharmacological effects and less side effects than known 1,4-dihydropyridine derivatives.
  • R 1 represents a 5- or 6-membered heterocyclic group having in the ring one or two hetero atoms selected from nitrogen, oxygen and sulfur atoms, said heterocyclic group may be substituted with halogen atom, trichloromethyl, trifluoromethyl, amino, acetylamino, benzoylamino, methoxy, ethoxy, propoxy, phenoxy, methoxy-carbonyl, ethoxycarbonyl, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl and tert-butyl and said heterocyclic group may be fused with a carbocyclic ring which may be substituted with methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, tert-butyl, methoxy, ethoxy and
  • pharmaceutically acceptable acid addition salt a salt, the anion of which is relatively innocuous to the animal organism when used in therapeutic doses, so that the beneficial properties of the cation are not vitiated by side-effects ascribable to the anion.
  • the compounds of the formula I wherein one of R 2 and R 3 represents a nitro group and the other represents a hydrogen atom are of the following formula:
  • the compounds of the present invention are those wherein R 1 is linked to an alkylene group through an ester bond (carbonyloxy group), which are different from the compounds wherein the heterocyclic group is linked to an alkylene group through an amide bond in an ester moiety at 3-position of 1,4-dihydro-2,6-dimethyl-4-phenylpyridine-3,5-dicarboxylic acid diesters as disclosed in the above-cited prior art WO 84/02132.
  • the compounds of the present invention are characterized by marked pharmacological effects as compared with the prior art compounds.
  • heterocyclic groups represented by R 1 include 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyranyl, 3-pyranyl, 4-pyranyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 3-isooxazolyl, 4-isooxazolyl, 5-isooxazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 2-imidazolyl, 4-imidazolyl, 2-morpholyl, 3-morpholyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, 2-pyrazyl, 3-pyridazyl and 4-pyridazyl.
  • Substituents for such heterocyclic groups include, e.g., fluorine, chlorine, bromine, iodine, trichloromethyl, trifluoromethyl, amino, acetylamino, benzoylamino, methoxy, ethoxy, propoxy, phenoxy, methoxycarbonyl, ethoxycarbonyl, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl and tert-butyl.
  • One or more such substituents are substituted on the carbon atom of the above heterocyclic groups.
  • Examples of the groups formed by fusion of the heterocyclic groups with a carbocyclic ring include 2-quinolyl, 3-quinolyl, 4-quinolyl, 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 2-quinazolyl, 4-quinazolyl and quinoxalyl .
  • substituents on the carbocyclic ring of these groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, tert-butyl, methoxy, ethoxy and propoxy .
  • Groups represented by R 4 of the above formula I include, e.g. methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, tert-butyl, methoxyethyl and ethoxyethyl ethoxyethoxymethyl .
  • the compounds of the present invention can be prepared by reacting a compound of the formula
  • the reaction is preferably conducted using reactants of the formulae II, III and IV in about equal mole amount to each other.
  • the proportions of the reactants used may be varied depending on the reaction conditions.
  • Examples of the compounds represented by the formula II include 2-nitrobenzaldehyde, 3-nitrobenzaldehyde, 2-trifluoromethylbenzaldehyde, 3-trifluoromethylbenzaldehyde and 2,3-dichlorobenzaldehyde .
  • Examples of the compounds represented by the formula III include methyl 3-amino crotonate, ethyl 3-aminocrotonate, n-propyl 3-aminocrotonate, i-propyl 3-aminocrotonate, n-butyl 3-aminocrotonate, i-butyl 3-aminocrotonate, tert-butyl 3-aminocrotonate, methoxymethyl 3-aminocrotonate, methoxyethyl 3-aminocrotonate, methoxypropyl 3-aminocrotonate, ethoxymethyl 3-aminocrotonate, ethoxyethyl 3-aminocrotonate, ethoxypropyl 3-aminocrotonate, propoxymethyl 3-aminocrotonate, propoxyethyl 3-aminocrotonate and propoxypropyl 3-aminocrotonate.
  • Examples of the compounds represented by the formula IV include those wherein n is 2 or 3, R 1 is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyrroyl, 3-pyrroyl, 2-pyranyl, 3-pyranyl, 4-pyranyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 3-isooxazolyl, 4-isooxazolyl, 5-isooxazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 2-imidazolyl, 4-imidazolyl, 2-morpholyl, 3-morpholyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, 2-pyrazyl, 3-pyridazyl and 4-pyridazyl, or these heterocyclic groups may be substituted with one or more substituents selected from fluorine, chlorine, bromine, iodine, trichloromethyl, trifluor
  • the reaction can be effected using an organic solvent as a reaction medium.
  • organic solvents include an alcohol such as methanol, ethanol, i-propanol or n-butanol; a lower dialkyl ether, e.g., diethylether; a cyclic ether such as tetrahydrofuran or dioxane; a lower dialkylformamide, e.g., dimethylformamide; dimethylsulfoxide; and a liquid heterocyclic base, e.g., pyridine.
  • the reaction may also be carried out in the absence of a reaction medium.
  • the reaction temperature can be from about 20 ° C to 150 C, preferably from 50 °C to 100 C.
  • the reaction can be effected at a temperature at which the reaction medium is boiling.
  • the reaction can be carried out at atmospheric pressure, optionally under elevated pressure.
  • the reaction is usually completed under the above reaction conditions during the time from 45 minutes to 10 hours.
  • the compounds of the present invention can be prepared by reacting a compound of the formula
  • Examples of the compounds represented by the formula V include those wherein n is 2 or 3; R 2 is hydrogen when R 3 is nitro or trifluoromethyl; or R 2 is nitro or trifluoromethyl when R 3 is hydrogen; or both R 2 and R 3 are chlorine; and further R 4 is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, tert-butyl, methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, propoxymethyl, propoxyethyl or propoxypropyl; and further X is chlorine, bromine, iodine, mesyloxy, benzenesulfonyloxy or tosyloxy.
  • Examples of the compounds represented by the formula VI include those wherein R 1 is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyranyl, 3-pyranyl, 4-pyranyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 3-isooxazolyl, 4-isooxazolyl, 5-isooxazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 2-imidazolyl, 4-imidazolyl, 2-morpholyl, 3-morpholyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, 2-pyrazyl, 3-pyridazyl and 4-pyridazyl; or these heterocyclic groups may be substituted with one or more substituents selected from fluorine, chlorine, bromine, iodine, trichloromethyl, trifluoromethyl, amino
  • the reaction can be carried out preferably in the presence of an inert organic solvent.
  • suitable solvents include, e.g., N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, hexamethyl phosphoamide, dioxane, acetonitrile, N-methylmorpholine and 1,2-dimethoxyethane .
  • the reaction temperature is suitably from 80 ° C to 160°C. Under the above conditions, the reaction is usually completed in a few hours.
  • compositions of the compounds of the formula I according to the present invention may be prepared by the application or adaptation of known methods for the preparation of salts of organic bases, for example, by reacting the compounds of the formula I with the appropriate acid in a suitable solvent.
  • addition salts include salts derived from inorganic and organic acids such as, without limitation, hydrochloric acid, phosphoric acid, sulfuric acid, acetic acid, tartaric acid, lactic acid, succinic acid, citric acid, maleic acid, sorbic acid, salicyclic acid and phthalic acid.
  • the new compounds may, depending on the choice of starting materials and process, be present as optical antipodes or racemate.
  • racemates obtained can be separated according to known methods, e.g., by means of microorganisms, or by a reaction with optically active acids forming salts of the compound, and separating the salts thus obtained, e.g., by means of the different solubility of the diastereomeric salts, from which the antipodes may be set free by the action of a suitable agent.
  • optically active acids are e.g., the L- and D-forms of tartaric acid, di-o-tolyltartaric acid, malic acid, mandelic acid, camphorsulfonic acid or quinic acid.
  • the more active part of the two antipodes is isolated.
  • the compounds of the present invention have marked inhibiting activity of calcium influx into cells as will be evident from the below-mentioned pharmacological test results, with the result of the use as vasodilator and antihypertensive agents.
  • the compounds of the present invention can be used for treatment of a variety of diseases including cardiac diseases such as angina pectoris, arrhythmia and acute heart failure, cerebrovascular diseases such as cerebral infarction and hypertension.
  • the compounds of the invention are usually administered orally, or parenterally in the form of a pharmaceutical preparation, which contains the active ingredient as free base in combination with pharmaceutically acceptable additives.
  • the additives may be a solid, semisolid or liquid diluent or a capsule.
  • These pharmaceutical preparations are a further object of the invention.
  • the amount of active ingredient is between 0.1 and 99% by weight of the preparation, suitably between 0.5 and 20% by weight in preparations for injection and between 2 and 50% by weight in preparations for oral administration.
  • the compound may be mixed with a solid, pulverulent additives, e.g., with lactose, saccharose, sorbitol, mannitol, starch, such as potato starch, corn starch, amylopectin, cellulose derivatives or gelatine, as well as with an lubricant such as magnesium stearate, calcium stearate, polyethyleneglycol or waxes, and be pressed into tablets.
  • a solid, pulverulent additives e.g., with lactose, saccharose, sorbitol, mannitol, starch, such as potato starch, corn starch, amylopectin, cellulose derivatives or gelatine, as well as with an lubricant such as magnesium stearate, calcium stearate, polyethyleneglycol or waxes, and be pressed into tablets.
  • a solid, pulverulent additives e.g., with lactose, saccharose, sorbi
  • Hard gelatine capsules may contain granules of the active compound in combination with a solid, pulverulent additives as lactose, saccharose, sorbitol, mannitol, starch (as, e.g., potato starch, corn starch or amylopectin), cellulose derivatives or gelatine.
  • a solid, pulverulent additives as lactose, saccharose, sorbitol, mannitol, starch (as, e.g., potato starch, corn starch or amylopectin), cellulose derivatives or gelatine.
  • Dosage units for rectal administration may be prepared in the form of suppositories, which contain the active ingredient in a mixture with a neutral fat base, or they may be prepared in the form of gelatine-rectal capsules which contain the active substance in a mixture with a vegetable oil or paraffin oil.
  • Liquid preparations for oral administration may be present in the form of sirups or suspensions, e.g., solutions containing from about 0.01% by weight to about 0.1% by weight of the active ingredient described, glycerol and propylene glycol.
  • the granules are sieved so that the particle size wanted is obtained. Under certain circumstances powder has to be removed.
  • the daily dose of the active ingredient varies and is dependent on the type of administration, but as a general rule it is 1 to 100 mg/day of active ingredient at peroral administration.
  • a syrup containing 0.5% (weight per volume) of active ingredient was prepared from the following ingredients: Sugar, d-sorbitol and the active ingredient were dissolved in 60 g of warm water. After cooling, glycerine and solution of flavouring agents dissolved in ethanol were added. To the mixture water was then added to 100 ml.
  • active ingredient may be replaced by other therapeutically active ingredients of the invention.
  • An active ingredient (50 mg) was mixed with lactose (50 mg), potato starch (20 mg) and colloidal silicic acid (9.5 mg). The mixture was moistened with a 10% solution of gelatine and was granulated through a 12- mesh sieve. After drying potato starch (10 mg), talc (0.75 mg) and magnesium stearate (0.75 mg) were admixed and the mixture thus obtained was pressed into tablets, each containing 50 mg of active ingredient. These tablets are coated with a 10% alcoholic solution of shellac and thereupon with an aqueous solution containing saccharose (45%), gum arabicum (5%), gelatine (4%) and dyestuff (0.2%). After the first five coatings talc and powdered sugar were used for powdering. The priming coat was then coated with a 66% sugar syrup and polished with a 10% carnauba wax solution in carbon tetrachloride.
  • Granules were prepared from active ingredient (50 mg), lactose (250 mg), potato starch (150 mg) and an alcoholic solution of polyvinylpyrrolidone (50 mg). After the drying step the granules were sieved through a 12 x 60 mesh sieve to prepare granules, each containing 50 mg of active ingredient.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)

Claims (19)

1. Verbindung der Formel I
Figure imgb0043
worin bedeuten:
R1 eine 5- oder 6-gliedrige heterocyclische Gruppe, die im Ring ein oder zwei Heteroatome, ausgewählt aus Stickstoff, Sauerstoff- und Schwefelatomen, enthält, wobei die heterocyclische Gruppe substituiert sein kann durch ein Halogenatom, Trichloromethyl, Trifluoromethyl, Amino, Acetylamino, Benzoylamino, Methoxy, Ethoxy, Propoxy, Phenoxy, Methoxycarbonyl, Ethoxycarbonyl, Methyl, Ethyl, n-Propyl, i-Propyl, n-Butyl, i-Butyl und tert-Butyl, und wobei die heterocyclische Gruppe kondensiert sein kann mit einem carbocyclischen Ring, der substituiert sein kann durch Methyl, Ethyl, n-Propyl, i-Propyl, n-Butyl, i-Butyl, tert-Butyl, Methoxy, Ethoxy und Propoxy;
R2 und R3 beide Halogenatome oder einer-der Reste R2 und R3 eine Nitro- oder Trifluoromethylgruppe und der andere ein Wasserstoffatom;
R4 eine geradkettige (unverzweigte) oder verzweigtkettige Methyl-, Ethyl-, n-Propyl-, i-Propyl-, n-Butyl-, i-Butyl-, sec-Butyl-, tert-Butyl-, Methoxymethyl-, Methoxyethyl-, Methoxypropyl-, Ethoxymethyl-, Ethoxyethyl-, Ethoxypropyl-, Propoxymethyl-, Propoxyethyl-, Propoxypropyl- oder Ethoxyethoxymethylgruppe und
n die Zahl 2 oder 3,

und ihr pharmazeutisch akzeptables Säureadditionssalz.
2. Verbindung nach Anspruch 1, worin R1 ausgewählt wird aus der Gruppe, die besteht aus 2-Furyl, 3-Furyl, 2-Thienyl, 3-Thienyl, 2-Pyrrolyl, 3-Pyrrolyl, 2-Pyranyl, 3-Pyranyl, 4-Pyranyl, 2-Pyridyl, 3-Pyridyl, 4-Pyridyl, 3-Isooxazolyl, 4-Isooxazolyl, 5-Isooxazolyl, 3-Isothiazolyl, 4-Isothiazolyl, 5-Isothiazolyl, 2-Imidazolyl, 4-Imidazolyl, 2-Morpholyl, 3-Morpholyl, 2-Pyrimidyl, 4-Pyrimidyl, 5-Pyrimidyl, 2-Pyrazyl, 3-Pyridazyl und 4-Pyridazyl.
3. Verbindung nach Anspruch 2, worin R1 die heterocyclische Gruppe bedeutet, die ein oder mehr Substituenten enthält, die ausgewählt werden aus der Gruppe, die besteht aus Fluor, Chlor, Brom, Jod, Trichloromethyl, Trifluoromethyl, Amino, Acetylamino, Benzoylamino, Methoxy, Ethoxy, Propoxy, Phenoxy, Methoxycarbonyl, Ethoxycarbonyl, Methyl, Ethyl, n-Propyl, i-Propyl, n-Butyl, i-Butyl und tert-Butyl.
4. Verbindung nach Anspruch 1, worin R1 ausgewählt wird aus der Gruppe, die besteht aus 2-Chinolyl, 3-Chinolyl, 4-Chinolyl, 1-Isochinolyl, 3-Isochinolyl, 4-Isochinolyl, 2-Chinazolyl, 4-Chinazolyl und Chinoxalyl, die substituiert sein kann durch Methyl, Ethyl, n-Propyl, i-Propyl, n-Butyl, i-Butyl, tert-Butyl, Methoxy, Ethoxy und Propoxy.
5. Verbindung nach Anspruch 2, 3 oder 4, worin einer der Reste R2 und R3 eine Nitrogruppe und der andere ein Wasserstoffatom darstellen und R4 ausgewählt wird aus der Gruppe, die besteht aus Methyl, Ethyl, n-Propyl, i-Propyl, n-Butyl, i-Butyl, sec-Butyl, tert-Butyl, Methoxyethyl, Ethoxyethyl und Ethoxyethoxymethyl.
6. Verbindung nach Anspruch 2, 3 oder 4, worin einer der Reste R2 und R3 eine Trifluoromethylgruppe und der andere ein Wasserstoffatom darstellen und R4 ausgewählt wird aus der Gruppe, die besteht aus Methyl, Ethyl, n-Propyl, i-Propyl, n-Butyl, i-Butyl, sec-Butyl, tert-Butyl, Methoxyethyl, Ethoxyethyl und Ethoxyethoxymethyl.
7. Verbindung nach Anspruch 2, 3 oder 4, worin R2 und R3 beide Halogenatome darstellen und R4 ausgewählt wird aus der Gruppe, die besteht aus Methyl, Ethyl, n-Propyl, i-Propyl, n-Butyl, i-Butyl, sec-Butyl, tert-Butyl, Methoxyethyl, Ethoxyethyl und Ethoxyethoxymethyl.
8. Verbindung nach Anspruch 5, worin R2 sich in der 2-Position befindet und eine Nitrogruppe darstellt.
9. Verbindung nach Anspruch 6, worin R2 sich in der 2-Position befindet und eine Trifluoromethylgruppe darstellt.
10. Verbindung nach Anspruch 7, worin R2 sich in der 2-Position befindet und R3 sich in der 3-Position befindet.
11. Verbindung nach Anspruch 1 bis 10, bei der es sich handelt um
1) 2,6-Dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridin - 3,5-dicarbonsäure - 3-(2-nicotinoyloxyethyl)-ester-5-methyl-ester;
2) 2,6,-Dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridin - 3,5-dicarbonsäure - 3-(2-nicotinoyloxyethyl)-ester-5-methyl-ester;
3) 2,6-Dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridin - 3,5-dicarbonsäure - 3-(2-picolinoyloxyethyl)-ester-5-methyl-ester;
4) 2,6-Dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridin - 3,5-dicarbonsäure - 3-(2-isonicotinoyloxyethyl)-ester-5-methyl-ester;
5) 2,6-Dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridin - 3,5-dicarbonsäure - 3-[2-(2-chloronicotinoy- loxy)ethyl]ester-5-methyl-ester;
6) 2,6-Dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridin - 3,5-dicarbonsäure - 3-(2-pyrazinoyloxyethyl)-ester-5-methyl-ester;
7) 2,6-Dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridin - 3,5-dicarbonsäure - 3-[2-(3-chinolin-carboxy)-ethyl]ester-5-methyl-ester;
8) 2,6-Dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridin - 3,5-dicarbonsäure - 3-(3-nicotinoyloxypropyl)-ester-5-methyl-ester;
9) 2,6-Dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridin - 3,5-dicarbonsäure - 3-[2-(3-thiophencarboxy)-ethyl]ester-5-methyl-ester;
10) 2,6-Dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridin - 3,5-dicarbonsäure - 3-[2-(3-furancarboxy)-ethyl]ester-5-methyl-ester;
11) 2,6-Dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridin - 3,5-dicarbonsäure - 3-[2-(6-chloronicotinoy- loxy)ethyl]ester-5-methyl-ester;
12) 2,6-Dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridin - 3,5-dicarbonsäure - 3-[2-(3-chinolin-carboxy)-ethyl]ester-5-methyl-ester;
13) 2,6-Dimethyl-4-(2-trifluoromethylphenyl)-1,4-dihydropyridin -3,5-dicarbonsäure - 3-(2-nicotinoy- loxyethyl)ester-5-methyl-ester;
14) 2,6-Dimethyl-4-(2-trifluoromethylphenyl)-1,4-dihydropyridin -3,5-dicarbonsäure - 3-[2-(6-chloroni- cotinoyloxy)ethyl]ester-5-methyl-ester;
15) 2,6-Dimethyl-4-(2-trifluoromethylphenyl)-1,4-dihydropyridin -3,5-dicarbonsäure - 3-[2-(3-chinolin- carboxy)ethyl]ester-5-methyl-ester;
16) 2,6-Dimethyl-4-(2,3-dichlorophenyl)-1,4-dihydropyridin - 3,5-dicarbonsäure - 3-(2-nicotinoyloxy- ethyl)ester-5-methyl-ester;
17) 2,6-Dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridin - 3,5-dicarbonsäure - 3-[2-(6-methylnicotinoy- loxy)ethyl]ester-5-methyl-ester;
18) 2,6-Dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridin - 3,5-dicarbonsäure - 3-[2-(6-aminonicotinoy- loxy)ethyl]ester-5-methyl-ester;
19) 2,6-Dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridin - 3,5-dicarbonsäure - 3-[2-(6-acetamidonicoti- noyloxy)ethyl]ester-5-methyl-ester;
20) 2,6-Dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridin - 3,5-dicarbonsäure - 3-[2-(-benzamidonicoti- noyloxy)-ethyl]ester-5-methyl-ester;
21) 2,6-Dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridin - 3,5-dicarbonsäure - 3-[2-(5-chloronicotinoy- loxy)ethyl]ester-5-methyl-ester;
22) 2,6-Dimethyl-4-(2-trifluoromethylphenyl)-1,4-dihydropyridin -3,5-dicarbonsäure - 3-[2-(6-methylni- cotinoyloxy)ethyl]ester-5-methyl-ester;
23) 2,6-Dimethyl-4-(2-trifluoromethylphenyl)-1,4-dihydropyridine-3,5-dicarbonsäure - 3-(2-nicotinoy- loxyethyl)ester-5-methoxyethyl-ester;
24) 2,6-Dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridin - 3,5-dicarbonsäure - 3-[2-(6-trichloromethylni- cotinoyloxy)ethyl]ester-5-methyl-ester;
25) 2,6-Dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridin - 3,5-dicarbonsäure - 3-[2-(6-iodonicotinoyloxy)-ethyl]ester-5-methyl-ester;
26) 2,6-Dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridin - 3,5-dicarbonsäure - 3-[2-(6-methoxynicotinoy- loxy)ethyl]ester-5-methyl-ester;
27) 2,6-Dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridin - 3,5-dicarbonsäure - 3-[2-(6-methoxycarbonyl- nicotinoyloxy)ethyl]ester-5-methyl-ester;
28) 2,6-Dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridin - 3,5-dicarbonsäure - 3-[2-(6-phenoxynicotinoy- loxy)ethyl]ester-5-methyl-ester;
29) 2,6-Dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridin - 3,5-dicarbonsäure - 3-(2-nicotinoyloxyethyl)-ester-5-ethyl-ester;
30) 2,6-Dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridin - 3,5-dicarbonsäure - 3-(2-nicotinoyloxyethyl)-ester-5-isopropyl-ester;
31) 2,6-Dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridin - 3,5-dicarbonsäure - 3-(2-nicotinoyloxyethyl)-ester-5-isobutyl-ester;
32) 2,6-Dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridin - 3,5-dicarbonsäure - 3-(2-nicotinoyloxyethyl)-ester-5-methoxyethyl-ester;
33) 2,6-Dimethyl-4-(2-trifluoromethylphenyl)-1,4-dihydropyridin -3,5-dicarbonsäure - 3-[2-(6-methox- ynicotinoyloxy)ethyl]ester-5-methyl-ester;
34) 2,6-Dimethyl-4-(2-trifluoromethylphenyl)-1,4-dihydropyridin -3,5-dicarbonsäure - 3-(2-nicotinoy- loxyethyl)ester-5-isobutyl-ester;
35) 2,6-Dimethyl-4-(2-trifluoromethylphenyl)-1,4-dihydropyridin -3,5-dicarbonsäure - 3-[2-(3-chinolin- carboxy)ethyl]ester-5-isobutyl-ester;
36) 2,6-Dimethyl-4-(2-trifluoromethylphenyl)-1 ,4-dihydropyridin -3,5-dicarbonsärue - 3-[2-(8-methyl-3-chinolin-carboxy)ethyl]ester-5-isobutyl_ester;
37) 2,6-Dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridin - 3,5-dicarbonsäure - 3-[2-(3-chinolin-carboxy)-ethyl]ester-5-methoxyethyl-ester;
38) 2,6-Dimethyl-4-(2-trifluoromethylphenyl)-1,4-dihydropyridin -3,5-dicarbonsäure - 3-[2-(3-chinolin- carboxy)ethyl]ester-5-methoxyethyl-ester;
39) 2,6-Dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridin - 3,5-dicarbonsäure 3-[2-(6-methoxy-3-chinolin- carboxy)ethyl]ester-5-methyl-ester;
40) 2,6-Dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridin - 3,5-dicarbonsäure - 3-[2-(8-methyl-3-chinolin- carboxy)ethyl]ester-5-methyl-ester;
41) 2,6-Dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridin - 3,5-dicarbonsäure - 3-[ 2-(3-chinolin-carboxy)-ethyl]ester-5-isobutyl-ester;
42) 2,6-Dimethyl-4-(2-trifluoromethylphenyl)-1,4-dihydropyridin -3,5-dicarbonsäure - 3-[2-(6-methoxy-3-chinolin-carboxy)ethyl]ester-5-isobutyl-ester;
43) 2,6-Dimethyl-4-(2-trifluoromethylphenyl)-1,4-dihydropyridin -3,5-dicarbonsäure - 3-[2-(6-methoxy-3-chinolin-carboxy)ethyl]ester-5-methyl-ester;
44) 2,6-Dimethyl-4-(2-trifluoromethylphenyl)-1,4-dihydropyridin -3,5-dicarbonsäure - 3-[2-(8-methyl-3 chinolin-carboxy)ethyl]ester-5-methyl-ester;
45) 2,6-Dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridin - 3,5-dicarbonsäure - 3-[2-(6-methoxy-3-chinolin-carboxy)ethyl]ester-5-isopropyl-ester;
46) 2,6-Dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridin - 3,5-dicarbonsäure - 3-[2-(4-chloronicotinoy- loxy)ethyl]ester-5-methyl-ester.
12. Pharmazeutisch akzeptable Säureadditionssalze einer Verbindung, wie sie in einem der Ansprüche 1 bis 11 angegeben ist.
13. Verfahren zur Herstellung einer Verbindung der Formel I, wie sie in Anspruch 1 definiert ist, dadurch gekennzeichnet, daß man
a) eine Verbindung der Formel
Figure imgb0044
worin R2 und R3 wie in Anspruch 1 definiert sind, umsetzt mit einer Verbindung der Formel
Figure imgb0045
worin R4 wie in Anspruch 1 definiert ist, und einer Verbindung der Formel
Figure imgb0046
worin R1 und n wie in Anspruch 1 definiert sind, oder
b) eine Verbindung der Formel
Figure imgb0047
worin R2, R3, R4 und n wie in Anspruch 1 definiert sind und X ein Halogenatom, eine Mesyloxygruppe, eine Benzolsulfonyloxygruppe oder eine Tosyloxygruppe darstellt, umsetzt mit einer Verbindung der Formel
Figure imgb0048
worin R1 wie in Anspruch 1 definiert ist und M ein Alkalimetall oder ein Erdalkalimetall bedeutet, und
c) anschließend an die Stufe (a) oder (b) gegebenenfalls durchführt eine Umwandlung der erhaltenen Verbindung der Formel (I) in ein pharmazeutisch akzeptables Additionssalz der Verbindung mit einer Säure durch Anwendung oder Anpassung bekannter Verfahren.
14. Pharmazeutische Zusammensetzung, die als aktiven Bestandteil (Wirkstoff) eine Verbindung nach Anspruch 1 oder 2 bis 11 oder ein pharmazeutisch akzeptables Additionssalz davon, gegebenenfalls im Gemisch mit Zusätzen für ein pharmazeutisches Präparat, enthält.
15. Pharmazeutische Zusammensetzung nach Anspruch 14, in welcher der aktive Bestandteil (Wirkstoff) die Verbindung nach Anspruch 5 oder das Säureadditionssalz derselben ist.
16. Pharmazeutische Zusammensetzung nach Anspruch 14, in der der aktive Bestandteil (Wirkstoff) die Verbindung nach Anspruch 6 oder das Säureadditionssalz derselben ist.
17. Pharmazeutische Zusammensetzung nach Anspruch 14, in der der aktive Bestandteil (Wirkstoff) die Verbindung nach Anspruch 7 oder das Säureadditionssalz derselben ist.
18. Pharmazeutische Zusammensetzung nach Anspruch 14, in der der aktive Bestandteil (Wirkstoff) eine der in Anspruch 11 genannten Verbindungen oder ein Säureadditionssalz derselben ist.
19. Pharmazeutische Zusammensetzung nach Anspruch 14 bis 18 für die Behandlung von Herzerkrankungen, Cerebrovasculärerkrankungen und Hypertension bei Säugetieren.
EP85115829A 1984-12-14 1985-12-12 1,4-Dihydropyridinderivate, Verfahren zu ihrer Herstellung und diese enthaltende pharmazeutische Zusammensetzungen Expired EP0184841B1 (de)

Applications Claiming Priority (8)

Application Number Priority Date Filing Date Title
JP262942/84 1984-12-14
JP26294284 1984-12-14
JP233349/85 1985-10-21
JP233350/85 1985-10-21
JP23335085 1985-10-21
JP23334985 1985-10-21
JP60269302A JPH0631223B2 (ja) 1984-12-14 1985-12-02 １，４−ジヒドロピリジン誘導体およびその製造法
JP269302/85 1985-12-02

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EP0184841A3 EP0184841A3 (en) 1987-09-02
EP0184841B1 true EP0184841B1 (de) 1992-11-11

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JPH0676405B2 (ja) * 1986-06-13 1994-09-28 日清製粉株式会社 １，４―ジヒドロピリジン誘導体およびそれを含有する医薬組成物
DE3617976A1 (de) * 1986-05-28 1988-01-14 Alter Sa 1,4-dihydropyridin, verfahren zu dessen herstellung und dessen verwendung in antithrombotischen medikamenten
DE3703963A1 (de) * 1987-02-10 1988-08-18 Hoechst Ag Pyridin-2,4- und 2,,5-dicarbonsaeure-derivate, verfahren zu ihrer herstellung, verwendung derselben, sowie arzneimittel auf basis dieser verbindungen
DE4003541C1 (de) * 1990-02-06 1991-08-08 Alter S.A., Madrid, Es
DE4233347A1 (de) * 1992-10-05 1994-04-07 Bayer Ag Dihydropyridin-alkoxy- und -alkylamino-aroylester
LV12200B (lv) * 1997-07-03 1999-04-20 Gunārs DUBURS Antidiabētisks līdzeklis
CN102464608B (zh) * 2010-11-15 2016-05-11 江苏先声药物研究有限公司 化合物及其作为l-型钙通道阻滞剂或/和乙酰胆碱酯酶抑制剂的应用

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DE1670824C3 (de) * 1967-03-20 1978-08-03 Bayer Ag, 5090 Leverkusen 1,4-Dihydropyridin-33-dicarbonsäurealkylester
DE2117571C3 (de) * 1971-04-10 1979-10-11 Bayer Ag, 5090 Leverkusen Unsymmetrische 1,4-Dihydropyridin-33-dicarbonsäureester, Verfahren zu ihrer Herstellung sowie ihre Verwendung als Arzneimittel
DE2218644C3 (de) * 1972-04-18 1982-08-19 Bayer Ag, 5090 Leverkusen Basische Ester von 1,4-Dihydropyridinen, Verfahren zu ihrer Herstellung sowie ihre Verwendung als Arzneimittel
DE2508181A1 (de) * 1975-02-26 1976-09-09 Bayer Ag 1,4-dihydropyridincarbonsaeurearal- kylester, verfahren zu ihrer herstellung sowie ihre verwendung als arzneimittel
FR2405937A1 (fr) * 1977-10-14 1979-05-11 Labaz Nouveaux derives de dihydropyridine, leur procede de preparation et leur application
SE429652B (sv) * 1978-06-30 1983-09-19 Haessle Ab 2.6-dimetyl-4-(2.3-diklorfenyl)-1.4-dihydropyridin-3.5-dikarboxylsyra-3-metylester-5-etylester
US4258042A (en) * 1980-04-11 1981-03-24 Usv Pharmaceutical Corporation Antihypertensive pyridines and compositions
DE3042769A1 (de) * 1980-11-13 1982-06-09 Bayer Ag, 5090 Leverkusen C-3 verknuepfte 1,4-dihydropyridine, ihre verwendung in arzneimitteln und verfahren zu ihrer herstellung
US4656181A (en) * 1982-11-24 1987-04-07 Cermol S.A. Esters of 1,4-dihydropyridines, processes for the preparation of the new esters, and medicaments containing the same

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ES8801543A1 (es) 1988-02-16
DE3586817T2 (de) 1993-03-25
EP0184841A3 (en) 1987-09-02
DE3586817D1 (de) 1992-12-17
ES557423A0 (es) 1988-02-16
US4757071A (en) 1988-07-12
EP0184841A2 (de) 1986-06-18

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